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Chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) are common and chronic disorders. COPD is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities and it is considered currently the fourth leading cause of death worldwide. DM is a systemic disease characterized by a chronic hyperglycemia associated with inflammation and oxidative stress. The relationship between the two conditions is not completely understood and conflicting results are reported in the literature. Many studies have investigated the mechanisms through with the respiratory disease is associated with an increased risk of metabolic condition or whether the incidence risk of COPD in individuals affected by DM is higher. The link between the two chronic conditions has relevant implications in the management of patients affected by the both of them. Respiratory patients should be screened for diabetes mellitus as a frequent comorbidity of lung disease since therapeutic options should be assessed about risk-to-benefit ratios associated with the indication for the steroid use. Furthermore, the role of hyperglycemia on pulmonary function (e.g. infection or inflammatory processes) should be evaluated in DM. Finally, in presence of both diseases potential treatment interactions should be considered. In this overview we explored the common aspects of both clinical chronic illnesses and investigated the interplay between the two conditions.

Since COVID-19 spread all over the world becoming a pandemic illness, researchers have better characterized route of virus transmissibility and clinical signs and symptoms of the disease. Since viral transmission occurs through the droplets emitted during coughing or sneezing, the lungs are primarily affected. However, SARS-CoV-2 can affect several human organs due to high expressions of ACE2 receptor which is the main viral target, and the virus may affect not only higher and lower respiratory tracts, but also heart, kidney, gastro enteric tract, liver, pancreas, nervous system and skin. This review focuses on extra pulmonary involvement underlying atypical presentation of COVID-19. There is a great body of evidence concerning several human organ abnormalities associated to the SARS-CoV-2, enough to consider COVID-19 as a multisystemic and polyhedral disease.

Introduction: Historically, asthma was considered a disease predominantly of the large airways, but gradually small airways have been recognized as the major site of airflow obstruction. Small airway dysfunction (SAD) significantly contributes to the pathophysiology of asthma, and it is present across all asthma severities. Promising preclinical findings documented enhanced beneficial effects of combination therapies on small airways compared to monocomponents, thus it was questioned whether this could translate into further clinical implications from bench-to-bedside. The aim of this review was to systematically assess the state of the art of small airway involvement in asthma, especially in response to different pharmacological treatments acting on the respiratory system., Evidence Acquisition: A comprehensive literature search was performed in MEDLINE for randomized controlled trials (RCTs) characterizing the impact on small airways of different pharmacological treatments acting on the respiratory system. The results were extracted and reported via qualitative synthesis., Evidence Synthesis: Overall, 63 studies were identified from the literature search, whereas 23 RCTs met the inclusion criteria. Evidence confirms that both drug particle size and the type of inhalation devices represent two of the most important variables for an effective peripheral lung distribution., Conclusions: Despite the numerous methodological tools to detect SAD, there is still no gold standard diagnostic method to assess small airways, especially in severe asthma. Further research should be directed to improve primary and secondary prevention strategies by supporting the combined approach of different non-invasive techniques for an early detection of peripheral abnormalities and optimization of asthma therapy.

Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma pathogenesis, the overexpression of several type 2 inflammatory mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with ASM hyperreactivity, all of which can be targeted by humanized monoclonal antibodies (mAbs). Therefore, the aim of this review was to systematically assess evidence across the literature on mAbs for the treatment of asthma with respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab were found to be effective in modulating the contractility of the ASM and preventing the AHR, but no available studies concerning the impact of reslizumab on the ASM were identified from the literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate the ASM in asthma, by specifically blocking the interaction between IgE, IL-4, and TSLP, and their receptors are located on the surface of ASM cells. Conversely, mepolizumab and benralizumab have prevalently indirect impacts against AHR by targeting eosinophils and other immunomodulatory effector cells promoting inflammatory processes. AHR has been suggested as the main treatable trait towards precision medicine in patients suffering from eosinophilic asthma, therefore, well-designed head-to-head trials are needed to compare the efficacy of those mAbs that directly target ASM contractility specifically against the AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab.

Purpose: Smoking-induced bronchiolitis with progressive small airway dysfunction (SAD) is a leading cause of chronic obstructive pulmonary disease. We investigated the value of using the impulse oscillometry system (IOS) to detect SAD in asymptomatic smokers with preserved spirometry., Patients and Methods: We included 75 asymptomatic smokers (37 females, mean age 47±12 years, 26±17 pack/year) with preserved spirometry [forced expiratory volume at 1st second (FEV1)/forced vital capacity (FVC) ≥0.70 and normal FVC] and 34 never-smokers (19 females, mean age 42±15 years)., Results: In smokers, pack/years were significantly related to spirometry and IOS parameters (p < 0.05). The values of the fall in resistance from 5 Hz to 20 Hz (R5 - R20) were significantly and inversely related to the values of the ratio of forced expiratory volume in 3 and in 6 seconds (FEV 3 /FEV 6 ) (p < 0.05). In addition, the percentage of heavy smokers (≥30 pack/year) with R5 - R20 >0.07 kPa·s·L -1 , considered as IOS index of SAD, but not with FEV3/FEV6 less than a lower limit of normal, a spirometry index of SAD, was significantly higher than that of mild smokers (<30 pack/year) and never-smokers (p < 0.05)., Conclusion: This study demonstrates that IOS has the potential to detect SAD in asymptomatic heavy smokers with preserved spirometry and with FEV3/FEV6 values in the normal range. We confirm that IOS provides parameters which can complement traditional measurements of pulmonary function., Competing Interests: The authors declare that they have no conflicts of interest for this work., (© 2021 Pisi et al.)

Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the current humanised monoclonal antibodies (mAbs) benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab have been proven to induce an OCS-sparing effect in randomized controlled trials (RCTs), thus overcoming the problem of OCS dependence in severe asthma. Nevertheless, a large discrepancy has been recognized between selected patients enrolled in RCTs and non-selected asthmatic populations in real-world settings. It is not possible to exclude that the OCS-sparing effect of mAbs resulting from the RCTs could be different than the real effect resulting in clinical practice. Therefore, we performed a systematic review and correlation analysis to assess whether mAbs are effective in eliciting an OCS-sparing effect and overcoming the OCS dependence in severe asthmatic patients in real-world settings. Overall, real-world studies support the evidence that OCS dependence is a real condition that, however, can be found only in a small number of really severe asthmatic patients. In most patients, the dependence on OCS can be related to modifying factors that, when adequately modulated, may lead to a significant reduction or suspension of OCS maintenance. Conversely, in severe asthmatics in whom OCS resistance is proved by a high daily dose intake, mAbs allow reversion of the OCS dependence, leading to the suspension of OCS therapy in most patients or >50% reduction in the daily OCS dose.

Introduction: In patients with chronic obstructive pulmonary disease (COPD), small airway dysfunction (SAD) is a key element and a functional consequence of the pathology. The exact role of SAD as a specific 'pharmacological target' represents an important research topic. Our objective was to ascertain whether an extra-fine formulation of beclomethasone dipropionate/formoterol fumarate (BDP/FF) NEXThaler ® 100/6 μg b.i.d. could improve SAD and, consequently, the quality of life of COPD patients., Methods: We enrolled COPD patients with severe airflow obstruction and at least one moderate exacerbation in the previous year, having started treatment with BDP/FF NEXThaler ® for no more than 1 week. Patients underwent three visits: at the start of the treatment (V1), 6 weeks (V2), and 12 weeks later (V3). At each visit, we evaluated the fall in resistance from 5 to 20 Hz (R5-R20) and residual volume/total lung capacity (RV/TLC) ratio by impulse oscillometry, spirometry, and plethysmography. The COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) questionnaire were also administered to assess the disease's impact on quality of life., Results: We enrolled 43 COPD patients (mean age 69 years, FEV 1 43%). R5-R20 significantly changed from baseline [0.23 ± 0.09 kPa/(l/s)] to V2 [0.16 ± 0.09 kPa/(l/s)] and V3 [0.16 ± 0.08 kPa/(l/s)] (p < 0.05). Clinical status was also significantly improved compared to baseline; in fact, CAT score changed from an average baseline value of 13-6 and 4 (V2 and V3, respectively) (p < 0.05). A correlation was found between CAT percentage change values and the corresponding ones of R5-R20 (r = - 0.329, p = 0.045) and RV/TLC (r = 0.354, p = 0.029)., Conclusions: In COPD patients, treatment with BDP/FF extra-fine formulation improved functional parameters related to small airway disease as well as the disease impact on health status., Trial Registration: ClinicalTrials.gov identifier, NCT04421742.

We report the case of a 46-year-old male patient who was referred for chest pain and bilateral pleural effusion. Despite treatment with antibiotics and steroids, the pleural effusion worsened over a few months until pulmonary function was halved. The CT scan showed bilateral pleural thickening with right basal opacity. Histology revealed extensive fibrotic tissue with focal collections of lymphocytes and giant cells without traces of asbestos bodies. Since no evidence of an infectious, embolic or occupational aetiology was found, this bilateral pleural effusion progressing to diffuse pleural thickening was diagnosed as cryptogenic fibrosing pleuritis, a rare pleural disease., Learning Points: Bilateral pleural effusion progressing to diffuse pleural thickening was diagnosed as cryptogenic fibrosing pleuritis, a rare pleural disease.Cryptogenic fibrosing pleuritis was treated with high-dose corticosteroids.The patient showed stable disease at 6-year follow-up., Competing Interests: Conflicts of Interests: The authors declare there are no competing interests., (© EFIM 2021.)

Background: The ventilation heterogeneity (VH) is reliably assessed by the multiple-breath nitrogen washout (MBNW), which provides indices of conductive (Scond) and acinar (Sacin) VH as well as the lung clearance index (LCI), an index of global VH. VH can be alternatively measured by the poorly communicating fraction (PCF), that is, the ratio of total lung capacity by body plethysmography to alveolar volume from the single-breath lung diffusing capacity measurement., Objectives: Our objective was to assess VH by PCF and MBNW in patients with asthma and with COPD and to compare PCF and MBNW parameters in both patient groups., Method: We studied 35 asthmatic patients and 45 patients with COPD. Each patient performed spirometry, body plethysmography, diffusing capacity, and MBNW test., Results: Compared to COPD patients, asthmatics showed a significantly lesser degree of airflow obstruction and lung hyperinflation. In asthmatic patients, both PCF and LCI and Sacin values were significantly lower than the corresponding ones of COPD patients. In addition, in both patient groups, PCF showed a positive correlation with LCI (p < 0.05) and Sacin (p < 0.05), but not with Scond. Lastly, COPD patients with PCF >30% were highly likely to have a value ≥2 of the mMRC dyspnea scale., Conclusions: These results showed that PCF, a readily measure derived from routine pulmonary function testing, can provide a comprehensive measure of both global and acinar VH in asthma and in COPD patients and can be considered as a comparable tool to the well-established MBNW technique., (© 2021 S. Karger AG, Basel.)

Background: Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder involving lungs, characterized by low serum concentration of the protein alpha-1 antitrypsin (AAT) also called proteinase inhibitor (PI). Asthma is common in AATD patients, but there are only few data on respiratory function in asthmatic patients with AATD., Objectives: The aim of the study was to evaluate lung function in asthmatic outpatients with mutation in the SERPINA1 gene coding for AAT versus asthmatic subjects without mutation., Methods: We performed the quantitative analysis of the serum concentration of AAT in 600 outpatients affected by mild to moderate asthma from the University Hospital of Parma, Italy. Fifty-seven of them underwent the genetic analysis subsequently; they were subdivided into mutated and non-mutated subjects. All the mutated patients had a heterozygous genotype, except 1 (PI*SS). We assessed the lung function through a flow-sensing spirometer and the small airway parameters through an impulse oscillometry system., Results: The values of forced vital capacity (% predicted) and those of the residual volume to total lung capacity ratio (%) were, respectively, lower and higher in patients mutated versus patients without mutation, showing a significantly greater air trapping (p = 0.014 and p = 0.017, respectively). Moreover, patients with mutation in comparison to patients without mutation showed lower forced expiratory volume in 3 s (% predicted) and forced expiratory volume in 6 s (L) spirometric values, reflecting a smaller airways contribution., Conclusions: In asthmatic patients, heterozygosity for AAT with PI*MZ and PI*MS genotypes was associated with small airway dysfunction and with lung air trapping., (© 2021 S. Karger AG, Basel.)

The novel coronavirus SARS-CoV-2 was first identified in Wuhan in December 2019 as cause of the consequent novel coronavirus disease 2019 (COVID-19). The virus has since spread worldwide. The clinical presentation following human infection ranges from a mild upper respiratory tract infection to severe acute respiratory distress syndrome and sepsis. We reviewed literature using Pubmed to identify relevant English-language articles published until April 15, 2020. Search terms include novel coronavirus pneumonia, severe acute respiratory syndrome coronavirus 2, coronavirus and ventilation. We summarized what SARS-CoV-2 infection means for the lungs.

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease of unknown origin that rapidly leads to death. However, the rate of disease progression varies from one individual to another and is still difficult to predict. The prognosis of IPF is poor, with a median survival of three to five years after diagnosis, without curative therapies other than lung transplantation. The factors leading to disease onset and progression are not yet completely known. The current disease paradigm is that sustained alveolar epithelial micro-injury caused by environmental triggers (e.g., cigarette smoke, microaspiration of gastric content, particulate dust, viral infections or lung microbial composition) leads to alveolar damage resulting in fibrosis in genetically susceptible individuals. Numerous epidemiological studies and case reports have shown that occupational factors contribute to the risk of developing IPF. In this perspective, we briefly review the current understanding of the pathophysiology of IPF and the importance of occupational factors in the pathogenesis and prognosis of the disease. Prompt identification and elimination of occult exposure may represent a novel treatment approach in patients with IPF.

Background: In patients with COPD, limited data have been reported concerning the association between dyspnea perception and exercise tests. Moreover, the perception of dyspnea has not been analyzed in patients with the same severity of air-flow obstruction. The aim of our study was to evaluate the relationship between the degree of dyspnea and exercise capacity in subjects with COPD who had the same severity of air-flow obstruction., Methods: We assessed dyspnea perception and maximum exercise capacity by using the modified Medical Research Council dyspnea scale (mMRC) questionnaire and by using the symptom-limited incremental cardiopulmonary exercise test, respectively. A propensity score matching was used to obtain the balance between the subjects with COPD and with an mMRC questionnaire score <2 and ≥2 (mMRC score) according to the severity of air-flow obstruction., Results: A total of 249 ambulatory adult patients with stable COPD (mean age, 68 y) were considered in the full cohort. After propensity score analysis, 160 subjects (65% men; mean ± SD FEV 1 , 47.5 ± 12.8% of predicted) were included in our study cohort. The subjects with an mMRC questionnaire score ≥2 in comparison with those with an mMRC questionnaire score <2 showed lower values in oxygen uptake at peak (V O 2 max) ( P = .002) and in maximum work load ( P < .001). In the regression models, the mMRC questionnaire score was able to predict oxygen uptake at peak ( P < .001) and at maximum work load ( P < .001)., Conclusions: In subjects with COPD and with the same severity of air-flow obstruction, a high score in dyspnea was related to a poor maximum exercise capacity. Our results support the view that, in COPD, the severity of air-flow obstruction was less informative than symptoms in the combined assessment of the disease., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2019 by Daedalus Enterprises.)

Objectives: This multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease-ILD, emphysema or neither)., Methods: Chest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ² test assessed the differences between groups. P<0.05 was considered statistically significant., Results: We enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6)., Conclusions: CPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD., Competing Interests: Competing interests: None declared.

Cough is a natural defense mechanism that protects the respiratory tract from inhaling foreign bodies and by clearing excessive bronchial secretions. As a spontaneous reflex arc, it involves receptors, an afferent pathway, a center processing information, an efferent pathway and effectors. The determinant factor of cough efficacy is the operational volume of the lung, which in turn relies on the strength and coordination of respiratory and laryngeal muscles as well as on lung mechanics. Respiratory muscle weakness and dysfunction as well as expiratory flow limitation and lung hyperinflation may occur in some neuromuscular disorders and in obstructive airway diseases, respectively. Accordingly, all these diseases may show an ineffective cough. In this brief overview, we deal with the determinants of the cough efficacy and the clinical conditions affecting cough efficacy as well as the cough's efficacy measurements in clinical setting.

The response to a bronchodilator is considered as crucial to diagnose COPD and to distinguish COPD from asthma. COPD is characterized by progressive airflow obstruction that is only partly reversible, whereas asthma is associated with airflow obstruction that is often reversible either spontaneously or with treatment. In spite of the partly reversible airflow obstruction, patients with COPD may show a significant bronchodilator response both in terms of an increase in forced expiratory volume in 1 second (FEV1) or in forced vital capacity (FVC) after an adequate dose of an inhaled bronchodilator. Changes in FEV1 or FVC characterize, respectively, flow or volume response after bronchodilator administration. This overview will deal with the reversibility testing characteristics and its clinical significance in COPD patients.

Background Heart rate recovery delay is a marker of cardiac autonomic dysfunction. In chronic obstructive pulmonary disease patients, the ventilatory response to exercise during incremental cardiopulmonary exercise test may add information about dynamic hyperinflation by low values of inspiratory capacity/total lung capacity ratio (at peak) and excess ventilation by the slope of minute ventilation to carbon dioxide output ratio (V E /V CO2 slope ). We aimed to assess if the ventilatory response to exercise might be a determinant for heart rate recovery delay. Design An observational, prospective study. Methods Anthropometric characteristics, lung function and cardiopulmonary exercise test data were recorded in chronic obstructive pulmonary disease outpatients. A cut-off of heart rate recovery of 12 or more beats was used to define heart rate recovery delay. Results Of 254 patients enrolled, 156 (61%) showed heart rate recovery delay. As compared to patients with normal heart rate recovery, patients with delay were older, with a worse lung function and with lower values of peak oxygen uptake, maximal workload, oxygen pulse at rest and at peak, and inspiratory capacity/total lung capacity at peak. Conversely, V E /V CO2 slope and dyspnoea and leg fatigue perception at peak were higher in patients with heart rate recovery delay. In the multivariate regression model adjusted for age, sex, fat-free mass, heart rate at rest and use of β-blockers, we found that inspiratory capacity/total lung capacity at peak (<0.25) (odds ratio 2.61; P = 0.007) and V E /V CO2 slope (>32) (odds ratio 2.26; P = 0.018) predict the risk of heart rate recovery delay. Conclusions In chronic obstructive pulmonary disease outpatients, heart rate recovery is associated with dynamic hyperinflation and excess ventilation during exercise.

Background: The Quantitative chest CT (QCT) is emerging as a promising tool in the assessment of interstitial lung disease (ILD). However, the precise relationship between QCT parameters and the fibrosis detectable in lung tissue, remains to be established. Objectives: The aim of this study was to compare QCT and histopathological features in patients with ILD. Moreover we verified if the QCT assessment is similar in patients with or without a ILD diagnosis proven by a biopsy. Methods: Twenty patients affected by ILD who underwent a chest CT and, later, a lung biopsy, were enrolled. Patients were divided according to the histopathological findings (IPF vs sarcoidosis) in two groups (respectively bIPF and bSarc). Other 20 patients with a radiological diagnosis of IPF were included in a control group (rIPF). All CTs were post-processed with a free software (Horos) in order to obtain an ILD quantitative assessment. Results: There were no differences in terms of gender, smoking habit and spirometric values between patients' groups. rIPF subjects were older than the other: 70 vs 59 and 47 years (p<0.001). A different distribution of QCT parameters was observed between bIPF and bSarc (p<0.01) while it was comparable within bIPF and rIPF. Conclusions: QCT parameters were similar in subjects affected by the same type of ILD detected with biopsy and with CT alone. These findings make stronger the assumption that QCT can identify the presence of pulmonary fibrosis and, ultimately, that it can represent an useful and effective tool to assess ILD. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 16-20) ., (Copyright: © 2018.)

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a recently described systemic inflammatory disease associated with elevated circulating levels of IgG4. IgG4-RD may affect one or more organs and lesions can present synchronously or metachronously in different organs. Pulmonary involvement of IgG4-related disease includes airway, lung parenchyma, pleura and mediastinum. In this article, we report two cases of IgG4-RD to show the multifaceted manifestations of this disease in the lungs. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 74-80) ., (Copyright: © 2018.)

It is now well established that the healthy bronchial tree contains a microbiome distinct from that of the upper respiratory tract and that the lung microbiome may be dysregulated in individuals with a chronic respiratory disease, such as asthma. In addition, after birth, gut microbes interact with the host tissue, especially with the lymphatic tissue, thereby guaranteeing efficient immune activation. This review focuses on the available literature on the relationships between the gut microbiome, immune function and asthma in childhood, as well as the therapeutic strategies aimed at acting on the modulation of the microbiome.

Introduction: A fixed-dose inhalation of a long-acting β-agonist (LABA) and inhaled corticosteroids (ICS) is commonly recommended for moderate to severe asthmatic patients not adequately controlled by an ICS only. In order to improve the patients' adherence and the control of disease there is a noteworthy interest for the next generation inhaled β adrenoreceptor agonists maintaining an over 24 hours bronchodilatation and used once-daily (ultra-LABAs). This review focuses on the currently available evidences on the clinical role of any single ultra-LABAs in the treatment of asthmatic patients. Areas covered: New ultra-LABAs have been developed in recent years for the treatment of asthma. In particular, several evidences in asthmatic patients include indacaterol, vilanterol, olodaterol, and abediterol. Expert opinion: Pharmacologically, all new ultra-LABAs considered have demonstrated a good ability to maintain a true bronchodilatation for over 24 hours and a good safety profile. This aspect could be a key point to improve the patient's perspective, the adherence to the treatment regimens and therefore the control of disease. At this time, however, limited data are available and no ultra-LABA+ICS may be recommended as preferred.

Background Silent/asymptomatic peripheral artery disease may occur in patients with chronic obstructive pulmonary disease, but it is poorly investigated. The primary aim of this study was to evaluate in chronic obstructive pulmonary disease patients the impact of asymptomatic/silent peripheral artery disease on maximal exercise capacity; the secondary aim was to search for predictors of peripheral artery disease. Methods We prospectively enrolled chronic obstructive pulmonary disease outpatients. Data on anthropometric characteristics, lung function, cardiopulmonary exercise test and ankle-brachial index were recorded. The cut-off of ankle-brachial index used to define patients with peripheral artery disease was ≤0.90. Results We studied 47 patients and found 24 patients (51%) who showed peripheral artery disease. As compared to patients without peripheral artery disease, patients with peripheral artery disease had lower values of peak oxygen uptake, peak workload, energy expenditure (metabolic equivalents) and heart rate recovery, but showed the same degree of airflow obstruction and static and dynamic hyperinflation. In a multivariate linear regression model performed to identify variables predicting metabolic equivalents, ankle-brachial index (β 2.59; 95% confidence interval 0.51-4.67; p = 0.016) was an independent variable. In the search for predictors of peripheral artery disease, heart rate recovery (odds ratio 8.80; 95% confidence interval 1.30-59.35; p = 0.026) increased the risk of peripheral artery disease, whereas metabolic equivalents (odds ratio 0.50; 95% confidence interval 0.26-0.94, p = 0.033) and inhaled corticosteroids+long-acting β 2 agonists (odds ratio 0.13; 95% confidence interval 0.02-0.83; p = 0.030) reduced this risk. Conclusions In chronic obstructive pulmonary disease outpatients, asymptomatic/silent peripheral artery disease affects the maximal exercise capacity regardless of airflow obstruction and lung hyperinflation. A delay of heart rate recovery increase the risk of peripheral artery disease, whereas high values of metabolic equivalents and the use of inhaled corticosteroids+long-acting β 2 agonists reduces this risk.

Background: Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications., Objectives: To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF., Outcomes: Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/β, FGF receptors 1 to 3, and VEGF receptors 1-3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression., Conclusions: The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Aim: Sarcoidosis is a systemic granulomatous inflammatory disease whose causes are still unknown and for which epidemiological data are often discordant. The aim of our study is to investigate prevalence and spatial distribution of cases, and identify environmental exposures associated with sarcoidosis in an Italian province., Methods: After georeferentiation of cases, the area under study was subdivided with respect to Municipality and Health Districts and to the altitude in order to identify zonal differences in prevalence. The bioaccumulation levels of 12 metals in lichen tissues were analyzed, in order to determine sources of air pollution. Finally, the analysis of the correlation between metals and between pickup stations was performed., Results: 223 patients were identified (58.3% female and 41.7% male of total) and the mean age was 50.6±15.4 years (53.5±15.5 years for the females and 46.5±14.4 for the males). The mean prevalence was 49 per 100.000 individuals. However, we observed very heterogeneous prevalence in the area under study. The correlations among metals revealed different deposition patterns in lowland area respect to hilly and mountain areas., Conclusions: The study highlights a high prevalence of sarcoidosis cases, characterized by a very inhomogeneous and patchy distribution with phenomena of local aggregation. Moreover, the bioaccumulation analysis was an effective method to identify the mineral particles that mostly contribute to air pollution in the different areas, but it was not sufficient to establish a clear correlation between the onset of sarcoidosis and environmental risk factors.

Background: In chronic obstructive pulmonary disease (COPD) patients, small-airway dysfunction (SAD) is considered a functional hallmark of disease. However, the exact role of SAD in the clinical presentation of COPD is not yet completely understood; moreover, it is not known whether SAD may have a relationship with the impact of disease., Objectives: To evaluate the prevalence of SAD among COPD patients categorized by the old and the new GOLD classification and to ascertain whether there is a relationship between SAD and impact of disease measured by the COPD Assessment Test (CAT) questionnaire., Methods: We prospectively enrolled COPD outpatients from the University Hospital of Parma. Using the impulse oscillometry system (IOS), we assessed the fall in resistance from 5 to 20 Hz (R5-R20), reactance at 5 Hz (X5), and resonant frequency (FRes) as markers of peripheral airway dysfunction. According to R5-R20 ≥0.07 or <0.07, the cohort was also categorized in patients with and without SAD, respectively., Results: We studied 202 patients. In both GOLD classifications, a progressive increasing distribution of R5-R20 and FRes was reported with a decreasing of X5. Moreover, there was a significant correlation between R5-R20 and CAT (r = 0.527, p < 0.001). Finally, the presence of SAD (OR 11.96; 95% CI 4.53-31.58; p < 0.001) and use of ICS + LABA + LAMA (OR 5.31; 95% CI 1.88-15.02; p = 0.002) were independent predictors of higher impact (CAT score ≥10)., Conclusion: In COPD patients, the presence of SAD, as assessed by IOS, progressively increases with GOLD classifications and it is closely related to the high impact of disease on health status., (© 2016 S. Karger AG, Basel.)

Background and Purpose: In Chronic Obstructive Pulmonary Disease (COPD) patients, the opportunity to carry out a thoracic high-resolution CT (HRCT) scan and to perform an incremental cardiopulmonary exercise test (CPET) increases the possibility to identify the different clinical features of disease. The aim of our study was to evaluate the relationships between HRCT metrics (on emphysema by low attenuation areas-LAA% and airways by wall area-WA%) and CPET variables related to the dynamic response to exercise in terms of elastic balance (Δ rest-to-peak IC/TLC) and ventilation capacity for carbon dioxide output (VE/VCO2slope and VE/VCO2 intercept)., Methods: We prospectively enrolled COPD outpatients from the University Hospital of Parma. Data on anthropometrics characteristics, lung function, HRCT (LAA% and WA%) and CPET (Δ rest-to-peak IC/TLC, VE/VCO2 slope and VE/VCO2 intercept) were recorded., Results: Fifty-one mild to moderate COPD patients (66% males; median age 70 y; mean FEV1 56% of pred.) were enrolled in the study. LAA% demonstrated a significant correlation with Δ rest-to-peak IC/TLC and VE/VCO2slope (r = 0.405, p = 0.005 and r = 0.453, p = 0.001, respectively), while WA% with VE/VCO2slope (r = -0.333, p = 0.020). In multivariate regression models, after adjustment for oxygen uptake (peak VO2) and physical capacity (peak workload), LAA was the only independent predictor of Δ rest-to-peak IC/TLC (β 0.774, SE 0.334, p = 0.025) and VE/VCO2 slope (β 0.155, SE 0.053, p = 0.005 and β 0.305, SE 0.123, p = 0.018, respectively). VE/VCO2 intercept was instead predicted from FEV1 only (β -0.097, SE 0.042, p = 0.027)., Conclusion: In mild to moderate COPD patients, emphysema (LAA) and airways metrics (WA) have close relationships with the different characteristics of ventilatory response to exercise. In particular, we were able to show that LAA is an independent predictor of exercise-induced Δ rest-to-peak IC/TLC and VE/VCO2 slope., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Data on cardiac alterations such as left ventricular (LV) hypertrophy, diastolic dysfunction, and lower stroke volume in patients with COPD are discordant. In this study, we investigated whether early structural and functional cardiac changes occur in patients with COPD devoid of manifest cardiovascular disease, and we assessed their associations with clinical and functional features., Methods: Forty-nine patients with COPD belonging to all Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes were enrolled and compared with 36 controls. All subjects underwent clinical history assessment, lung function testing, blood pressure measurement, electrocardiography, and conventional and Doppler tissue echocardiography. Patients were also subjected to computed tomography to quantify emphysema score., Results: Patients with COPD had lower LV cavity associated with a marked increase in relative wall thickness (RWT), suggesting concentric remodeling without significant changes in LV mass. RWT was significantly associated with ratio of the forced expiratory volume in 1 second to the forced vital capacity and emphysema score and was the only cardiac parameter that - after multivariate analysis - significantly correlated with COPD conditions in all individuals. Receiver operating characteristic curve analysis showed that RWT (with a cutoff point of 0.42) predicted the severity of COPD with 83% specificity and 56% sensitivity (area under the curve =0.69, 95% confidence interval =0.59-0.81). Patients with COPD showed right ventricular to be functional but no structural changes., Conclusion: Patients with COPD without evident cardiovascular disease exhibit significant changes in LV geometry, resulting in concentric remodeling. In all individuals, RWT was significantly and independently related to COPD. However, its prognostic role should be determined in future studies.

Background: Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma., Methods: In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095., Findings: Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated., Interpretation: In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small., Funding: Italian Medicines Agency., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Bronchial asthma remains one of the most common chronic diseases in the world; approximately 10% of patients shows exacerbations severe enough to be judged life-threatening, whereas around 2-20% of patients are admitted to the Intensive Care Unit (ICU). Acute severe asthma is a dangerous condition where the deterioration of the asthmatic exacerbation usually progresses over days or weeks, although in a few patients over hours or even minutes. Morbidity and mortality are mainly related to the underestimation of the severity of the exacerbation, delay in referring to hospital and inadequate emergency treatment. The cornerstone measures of therapy for acute severe asthma are oxygen supplementation, as to achieve arterial saturation &gt;90%, and repetitive or continuous administration of bronchodilators (short-acting inhaled β2-agonists and ipratropium bromide) and corticosteroids. Despite extensive clinical experience in treatment of chronic asthma with steroids, there is considerable uncertainty about the accurate use of these agents for treatment of acute severe asthma in emergency settings.

The T lymphocyte-mediated immune response to Mycobacterium tuberculosis infection in the parietal pleura of patients with tuberculous pleurisy is unknown. The aim of this study was to investigate the immune response in the parietal pleura of tuberculous pleurisy compared with nonspecific pleuritis. We have measured the numbers of inflammatory cells particularly T-cell subsets (Th1/Th2/Th17/Treg cells) in biopsies of parietal pleura obtained from 14 subjects with proven tuberculous pleurisy compared with a control group of 12 subjects with nonspecific pleuritis. The number of CD3+, CD4+ and CCR4+ cells and the expression of RORC2 mRNA were significantly increased in the tuberculous pleurisy patients compared with the nonspecific pleuritis subjects. The number of toluidine blue+ cells, tryptase+ cells and GATA-3+ cells was significantly decreased in the parietal pleura of patients with tuberculous pleurisy compared with the control group of nonspecific pleuritis subjects. Logistic regression with receiver operator characteristic (ROC) analysis for the three single markers was performed and showed a better performance for GATA-3 with a sensitivity of 75%, a specificity of 100% and an AUC of 0.88. There was no significant difference between the two groups of subjects in the number of CD8, CD68, neutrophil elastase, interferon (IFN)-γ, STAT4, T-bet, CCR5, CXCR3, CRTH2, STAT6 and FOXP3 positive cells. Elevated CD3, CD4, CCR4 and Th17 cells and decreased mast cells and GATA-3+ cells in the parietal pleura distinguish patients with untreated tuberculous pleurisy from those with nonspecific pleuritis.

Aims: Epidemiological studies show that peak exposure to air pollution is associated with increased morbidity and mortality from cardiovascular events. Panel and controlled exposure studies show that particulate matter (PM) may influence the parasympathetic regulation of the heart. The aim of this study was to concurrently measure individual exposure to PM of various sizes, heart rate variability (HRV), and electrical instability in patients with myocardial infarction., Methods and Results: Personal exposures to PM(10), PM(2.5), and PM(0.25) was measured over 24 h in 39 patients (36 males, 3 females; mean age 60.3 years) with prior myocardial infarction (>6 months). Simultaneously, a 24 h ECG was recorded and then analysed for HRV and ventricular arrhythmias. Breath condensate and blood samples also were collected at the end of monitoring to measure several indexes of inflammation. Negative correlation was found between HRV and exposure to PM(0.25) in a group of patients not taking beta-blockers. More severe ventricular arrhythmias were observed at the highest concentrations of PM(10) and PM(2.5). Indexes of inflammation in either breath condensate or blood did not correlate with PM exposures., Conclusion: Our study shows that exposure to ultrafine particles is associated with autonomic dysregulation in selected patients with myocardial infarction. More severe arrhythmias occur at the highest exposures to larger particles. Nevertheless, the underlying mechanisms remain hypothetical because inflammation may be evoked by PM or be related to the disease itself.

Background and Objectives: Acute respiratory distress syndrome (ARDS) is a frequent form of hypoxiemic respiratory failure caused by the acute development of diffuse lung inflammation. Dysregulated systemic inflammation with persistent elevation of circulating inflammatory cytokines is the pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with ARDS. Glucocorticoids (GCs) have a broad range of inhibitory inflammatory effects, including inhibition of cytokines transcription, cellular activation and growth factor production. They inhibit the inflammatory pathways through two specific intracellular glucocorticoid receptors (GRs), named GR alpha and GR beta. The aim of our study was to evaluate the histologic evidence of inflammatory injury and the GR alpha uptake of resident and inflammatory cells in different experimental models of acute lung injury (ALI)., Methods: We studied four groups of rats: three different experimental rat models of lung injury and a control group. The ALI was caused by barotrauma (due to an overventilation), oleic acid injection and mechanical ventilation. Results were compared to nonventilated rat control group. The duration of mechanical ventilation was of 2.5h. At the end of each experiment, rats were sacrificed. Lung biopsies were evaluated for morphologic changes. The immunohistochemistry was performed to study GR alpha expression., Results: Histologic evidence of lung injury (alveolar and interstitial edema, vascular congestion, alveolar haemorrhage, emphysema, number of interstitial cells and neutrophils, and destruction of alveolar attachments) were present in all ventilated groups. Barotrauma lead to an additional inflammatory response. GR alpha expression significantly increased in the three ventilated groups compared with nonventilated groups. GR alpha expression was highest in barotrauma group., Conclusions: These data indicate that ALI is associated with diffuse alveolar damage, up-regulation of the inflammatory response and GR alpha overexpression. Barotrauma is the most effective mechanism inducing acute lung inflammation and GR alpha overexpression.

Exhaled breath condensate (EBC) is composed mainly by water and also contains non-volatile mediators, which are expired in small droplets of airway fluid. Urea has been proposed as a normalization factor for EBC non-volatile biomarkers. Aim of this study was to assess volatility and diffusivity of urea ex vivo and to measure its EBC concentrations in different clinical conditions. Volatility was assessed quantifying EBC concentrations collected at 4 different temperatures, whereas diffusivity was tested by measuring urea concentrations in both plasma and EBC from uraemic patients on intermittent haemodialysis. Urea was also measured in EBC from patients with chronic airway diseases, i.e., chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The concentration of urea but not its absolute amount in EBC increased with condensation temperature. Haemodialysis influenced EBC and plasma urea concentrations in a similar way. The concentrations of urea in chronic airway diseases did not significantly differ from those of controls. Urea is a non-volatile molecule ex vivo and EBC urea depends on its concentrations in plasma. Urea concentrations in EBC are unaffected by three chronic airway diseases. We suggest that there is no need to normalize non-volatile biomarkers in EBC for urea concentrations to account for inter-individual variability. However, in repeated measurements within the same individual, the use of urea either as a normalizing factor or as covariate variable could be proposed to control intra-individual variability.